Bone matrix is a storehouse of growth factors. Bone is the most abundant source of transforming growth factor beta (TGFbeta), one of the most active bone- derived growth factors in the body. TGFbeta is a multifunctional factor with potent and powerful effects on both osteoblasts and osteoclasts. It has been suggested that TGFbeta acts as a coupling factor that is responsible for initiating new bone formation after previous bone resorption. TGFbeta is stored in bone in a latent, or inactive form. This matrix latent form has not been characterized. The latent complex found in the matrix contains a protein for which several functions have been hypothesized which may be particularly relevant to bone formation. The applicant suggests that her data shows that this protein (called the TGFbeta binding protein; LTBP) is an extracellular matrix protein which, together with TGFbeta, forms fibrillar structures, both in vivo and in vitro. LTBP is necessary for the formation of bone-like mineralized nodules in vitro. The LTBP fibrils appear in culture before, and are distinctly different from, collagen type I fibers and therefore may be one of the earliest expressed proteins in bone formation. In this study, the functional role of LTBP in new bone formation will be examined. The expression of both TGFbeta and LTBP during new bone formation will be compared with expression of other well-known markers of bone cell differentiation such as alkaline phosphatase, osteopontin, and osteocalcin in cultures of fetal rat calvarial cells. The effects of osteotropic factors, namely parathyroid hormone, bone morphogenetic protein 2 and TGFbeta, on TGFbeta and LTBP expression will also be examined. The mechanisms whereby latent TGFbeta is targeted to bone, and the molecular and cellular mechanisms whereby latent and active TGFbeta are released from bone will be investigated. Synthetic peptides which block LTBP fibril formation and consequently bone formation will be developed. Dominant-negative LTBP constructs will be designed and tested. Understanding these mechanisms may lend insight into the interactions between osteoclasts and osteoblasts during bone remodeling, and into the mechanisms of normal osteoblastic bone formation.
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